Date of Award
Doctor of Philosophy (PhD)
The sinoatrial node of the mouse embryo arises from the wall of the right atrium near the border of the sinus venosus. Early in development this region expresses the transcription factor Tbx5. Because of this, Tbx5 is thought to sit at the apex of a transcriptional cascade leading to sinoatrial node (SAN) differentiation. To test this we produced a mouse embryonic stem cell line B1 (pTripZ-mTbx5; αMHC::GFP) that conditionally overexpresses Tbx5, to determine if this would lead to enhanced SAN differentiation. We found that ES cells overexpressing Tbx5 showed enhanced overall cardiac differentiation and that cardiac cells showed increased beat rates as compared control embryos. Despite this, key genes associated with SAN differentiation including HCN4 and Shox2 increased in cells overexpressing Tbx5, while the percent of HCN4 or Shox2 positive myocytes did not alter. Faster beating cells showed a decreased expression of the chamber specific marker Cx43 and increased expression of Tbx3 and Tbx18. These data suggest that Tbx5 overexpression is not sufficient for SAN differentiation, although it does activate part of the transcriptional cascade that directs early steps in the SAN. Together these data suggest that Tbx5 cannot activate SAN differentiation alone but instead must synergize with other factors.
Dai, Yunkai, "The Role of Tbx5 in Sinoatrial Node Differentiation in Mouse Embryonic Stem Cell Derived Cardiomyocytes" (2019). All Dissertations. 2377.